The preparation method of imatinib
An amino, methylphenyl technology, applied in the field of preparation of imatinib, can solve problems such as reduced reaction yield, and achieve the effects of high purity, low production cost, and low equipment requirements
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[0023] This application relates to the preparation method of imatinib (I), said method comprises the following steps: using dichloromethane as organic solvent, taking triethylamine as base, making N-(5-amino-2-methylphenyl )-4-(3-pyridyl)-2-aminopyrimidine is reacted with 4-(4-methylpiperazinemethyl)benzoyl chloride dihydrochloride to form imatinib.
[0024] The reaction scheme is:
[0025]
[0026] where TEA represents triethylamine.
[0027] In certain embodiments of the present application, N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine and 4-(4-methylpiperazinemethyl ) The reaction molar ratio of benzoyl chloride dihydrochloride is 0.9-2.0:1.0, preferably 0.9:1.0-1.0:1.0.
[0028] Those skilled in the art can select the appropriate amount of organic solvent dichloromethane in the reaction according to the needs of practice, for example, its amount can be the conventional amount used in organic synthesis reactions. In certain embodiments of the present app...
Embodiment 1
[0065] Example 1: 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-yl] Preparation of amino]phenyl]benzamide (I)
[0066] N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine (150.0 g, 0.54 mol) was added to dichloromethane (3000.0 g), followed by triethyl Amine (164.0 g, 1.62 mol), heated to 30°C with stirring. 4-(4-Methylpiperazinemethyl)benzoyl chloride dihydrochloride (193.6 g, 0.60 mol) was added in portions as a solid. After the addition, the reaction solution was incubated for 3 hours, and TLC monitoring showed that the reaction was basically complete. Cool the reaction solution to room temperature, add 2 mol / L sodium hydroxide aqueous solution (1500 g), and stir until all solids are dissolved, and the pH value is greater than 14 at this time. After standing to separate the layers, the organic phase was separated. The aqueous phase was extracted with dichloromethane (1500.0g×2), the organic phases were combined, washed once with s...
Embodiment 2
[0070] Example 2: 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-yl] Preparation of amino]phenyl]benzamide (I)
[0071] N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine (1.50kg, 5.4mol) was added to dichloromethane (30.0kg), then triethyl Amine (1.64kg, 16.2mol), stirred and heated to 30°C. 4-(4-Methylpiperazinemethyl)benzoyl chloride dihydrochloride (1.94 kg, 6.0 mol) was added as a solid in portions. After the addition, the reaction solution was incubated for 8 hours, and TLC monitoring showed that the reaction was basically complete. Cool the reaction solution to room temperature, add 2 mol / L sodium hydroxide solution (15.0 kg), and stir until all solids are dissolved, and the pH value is greater than 14 at this time. After standing to separate the layers, the organic phase was separated. The aqueous phase was extracted with dichloromethane (10.0kg×2), the organic phases were combined, washed once with saturated saline solution,...
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